Hepatotoxicity In Mice Research Articles

Cadmium-Induced Hepatotoxicity in Mice – Prophylactic Supplementation of Quercetin Exerts Hepatoprotective Effect by Modulating PI3K/Akt/NF-κB Signaling Pathway

This current study seeks to examine the pre-protective function of Quercetin in Cadmium (Cd)-induced liver damage, along with its modulation of the PI3K/Akt/NF-κB signaling pathway. A total of 60 male C57BL/6J mice were randomly assigned to four groups: control (C), quercetin (Q, 100 mg/kg/day), Cd (Cd, 2.5 mg/kg/day), and quercetin and Cd (Q+Cd). Before receiving Cd treatment, quercetin was administered intragastrically for 4 weeks. In the present study, liver markers, oxidative stress parameters, pro-inflammatory cytokines, liver histopathology, apoptotic markers and PI3K/Akt/NF-κB signaling molecules were examined. We observed that the body weight of the Cd-treated mice dramatically rise after 4 weeks of quercetin pre-administration, and the Cd concentration was significantly decreased. Liver function markers like alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and lactate dehydrogenase (LDH) were significantly reduced in quercetin treatment in Cd-induced mice. Additionally, we observed that quercetin reduced Cd-mediated liver injury in mice by assessing the level of malondialdehyde (MDA), and the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) concentrations and the histological alterations. By monitoring tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β), quercetin successfully reduced the inflammatory cytokines that the Cd metal caused in the liver. Additionally, in the liver tissues of Cd-mediated, quercetin could enhance the expression of Bcl-2 and decrease the expression of p-Akt, p-PI3K, Bax, Caspase-9, Caspase-3, NF-κB. In conclusion, quercetin protects against Cd induced liver injury via several pathways, including oxidative stress, inflammation and apoptosis, and its protective effect correlates with antioxidant activity.

Zingerone effects on arsenic-induced glucose intolerance and hepatotoxicity in mice via suppression of oxidative stress-mediated hepatic inflammation and apoptosis

Zingerone effects on arsenic-induced glucose intolerance and hepatotoxicity in mice via suppression of oxidative stress-mediated hepatic inflammation and apoptosis

Hepatotoxicity Induced by Methyl Eugenol: Insights from Toxicokinetics, Metabolomics, and Gut Microbiota.

Due to continuous application as a flavoring agent in the pesticide, pharmaceutical, and food industries, methyl eugenol (ME) persists in the environment and causes deleterious impacts including cytotoxicity, genotoxicity, and liver damage. This study utilized a comprehensive approach, integrating toxicokinetics, metabolomics, and gut microbiota analysis, to explore the mechanisms behind ME-induced hepatotoxicity in mice. The study observed significant rises in ALT and AST levels, along with significant weight loss, indicating severe liver damage. Toxicokinetic data showed delayed Tmax and plasma accumulation after 28 days of repeated ME exposure at doses of 20 mg/kg, 40 mg/kg, and 60 mg/kg. The metabolomic analysis pinpointed four critical pathways-TCA cycle; alanine, aspartate, and glutamate metabolism; arginine biosynthesis; and tyrosine metabolism-linked to 20 potential biomarkers. Gut microbiota analysis revealed that extended ME exposure led to microbial imbalance, particularly altering the populations of Akkermansia, Prevotella, and Ruminococcus, which are key to amino acid metabolism and the TCA cycle, thus contributing to hepatotoxicity. However, the causal relationship between changes in gut microbiota and liver metabolite levels still requires further in-depth research. This study underscores the significant role of liver metabolites and gut microbiota in ME-induced liver damage.

Artemisia Argyi essential oil ameliorates acetaminophen-induced hepatotoxicity via CYP2E1 and γ-glutamyl cycle reprogramming

BackgroundThe hepatotoxicity induced by acetaminophen (APAP), a commonly used antipyretic, analgesic and anti-inflammatory drug in clinical practice, has received accumulated attention. Artemisia argyi essential oil (AAEO), a volatile oil component extracted from traditional Chinese medicine Artemisia argyi H.Lév. & Vaniot, has great hepatoprotective effects. However, the potential role of AAEO in APAP-induced hepatotoxicity has not been characterized. The present study aimed to investigate the effects of AAEO on hepatic metabolic changes in mice exposed to APAP. MethodsIn this study, 300.00 mg/kg acetaminophen was used to establish liver injury model in C57BL/6 J mice. Hepatoprotective effect of AAEO on APAP-induced hepatotoxicity in mice was investigated by detecting liver function enzymes and histopathological examination. Secondly, UPLC-MS/MS was used to analyze the to analyze the small molecule metabolites and metabolic pathways induced by AAEO treatment; In addition, the effect of AAEO on APAP-induced oxidative stress and inflammation were evaluated by detecting the levels of glutathione peroxidase 4, malondialdehyde, reactive oxygen species and inflammatory factors. Finally, the active components of AAEO were preliminarily screened by cellular assays. The hepatoprotective effect of AAEO against APAP-induced hepatotoxicity was examined through the Western blotting, after the CYP2E1 gene was knocked down in AML12 cells by siRNA transfection. ResultsCompared with the APAP group, AAEO could reduce the abnormal increase in the levels of liver function enzymes caused by APAP. AAEO could enhance the antioxidant capacity by down-regulating the biosynthesis pathway of unsaturated fatty acids and promoting the activity of antioxidant enzymes SOD and CAT in liver tissue induced by APAP. Our study revealed that AAEO promoted GSH synthesis and covalently combined to form APAP-GSH conjugates to reduce the accumulation of APAP in liver tissue. In addition, the chemical constituents in AAEO were analyzed by GC–MS/MS, and it was determined to identify that dihydro-beta-ionone and (-)-verbenone in AAEO might have a significant protective effect on hepatocyte survival after APAP exposure. Further studies on the hepatoprotective mechanism of AAEO indicated that it might reduce the production of toxic metabolites by regulating CYP2E1 levels. ConclusionAAEO exerted hepatoprotective effects on acetaminophen-induced hepatotoxicity in mice via regulating the activity of CYP2E1 and regulating the γ-glutamyl cycle pathway.

Evaluation of the hepatoprotective effect of curcumin alone or in combination with vitamin C in methotrexate-induced hepatotoxicity in mice.

To assess the hepatoprotective effect of curcumin and/or vitamin C in methotrexate-induced hepatotoxicity. The experimental study was conducted at the Department of Pharmacology, College of Medicine, and the Iraqi Centre for Cancer and Medical Genetic Research, Mustansiriya University, Baghdad, Iraq, from Nov 12, 2020, to June 1, 2021, and comprised Swiss albino female mice aged 3-4 months and weighing 30-40g each. The mice were divided into 5 groups and treated for 10 days. Group 1 received distilled water, group 2 received single-dose methotrexate on the 10th day of the trial, group 3 was treated with curcumin plus methotrexate, group 4 was treated with vitamin C plus methotrexate, and group 5 was treated with curcumin and vitamin C plus methotrexate. Parameters measured were serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and lactate dehydrogenase, as well as hepatic tissue malondialdehyde, superoxide dismutase and glutathione. Data was analysed using SPSS 16. There were 35 mice; 7(20%) in each of the 5 groups. Hepatoprotection produced by curcumin as reflected by a decrease in lactate dehydrogenase and malondialdehyde levels was significant (p<0.05). Vitamin C also produced a significant hepatoprotection, demonstrated by a decrease in alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase and malondialdehyde levels. The combination of curcumin and vitamin C reflected an additive effect demonstrated by a significant decrease in malondialdehyde (p<0.05). Curcumin and/or vitamin C provided hepatoprotection against methotrexate-induced hepatotoxicity through modulation of oxidative stress biomarkers.

Some histone deacetylase inhibitors protect against dextran sulphate sodium-induced hepatotoxicity in mice

Some histone deacetylase inhibitors protect against dextran sulphate sodium-induced hepatotoxicity in mice

Nicorandil attenuates lithocholic acid-induced hepatotoxicity in mice through impeding oxidative stress, inflammation and apoptosis

This study was performed to explore the beneficial protective impact of nicorandil (Nico) against lithocholic acid (LCA)-induced hepatotoxicity. Materials and methods: Mice received Nico (50 and 100 mg/kg. orally) for 7 days and LCA (125 mg/kg, i.p.) was injected for the last 4 days two times daily. Results: Nico improved both structural and functional abnormalities induced by LCA. Nico significantly decreased serum levels of transaminases, ALP, GGT and markedly elevated albumin levels. Additionally, Nico mitigated oxidative stress; it decreased contents of MDA and NO and increased GSH level and SOD activity. Moreover, Nico markedly decreased the elevated levels of TNF-α, JNK, Bax, Caspase-3 and iNOS, and increased the levels of eNOS in hepatic tissues. Furthermore, Nico substantially decreased the expression of NFκBp65 in hepatic tissues. Histopathological and transmission electron microscopy findings further supported these biomarkers. Conclusion: Nico might be used as an adjuvant medication to prevent LCA-induced hepatotoxicity, pending further clinical research, through impeding oxidative stress, inflammation and apoptosis.

Efficacy of DHA-enriched phosphatidylserine and its underlying mechanism in alleviating polystyrene nanoplastics-induced hepatotoxicity in mice

ObjectivePlastic pollution has become a global pollution problem that cannot be ignored. As the main destination of human oral intake, the toxic effects of plastic on the digestive system represented by the intestine and liver are the focus of current research. Marine-derived DHA-PS has a variety of biological activities, mainly focusing on improving brain function and regulating lipid metabolism. However, whether it has an improvement effect on PS-NPs-induced hepato-intestinal injury and the underlying mechanism remain unclear. MethodsA murine liver injury model was established by gavage of PS-NPs for six weeks. By integrating approaches from lipidomics, transcriptomics, and gut microbiota analysis, the molecular mechanism by which DHA-PS alleviates PS-NPs-induced murine hepatotoxicity was explored through the “gut-liver axis”. ResultsOur findings reveal that prolonged exposure to PS-NPs results in significant murine liver damage and dysfunction, characterized by increased oxidative stress and inflammation, along with exacerbated hepatic lipid accumulation. Mechanistically, PS-NPs disrupt the hepatic SIRT1-AMPK pathway by suppressing the expression of SIRT1, AMPKα, and PPARα, while enhancing the expression of SREBP-1c, ultimately leading to disordered hepatic lipid metabolism. The sphingolipid and glycerophospholipid metabolic pathways were particularly affected. Additionally, in agreement with transcriptomic analyses, PS-NPs activate the hepatic TLR4/NF-κB pathway. At the same time, exposure to PS-NPs decreases the expression of ZO-1, occludin, and claudin-1, diminishes the relative abundance of beneficial gut bacteria (norank_f_Muribaculaceae, Akkermansia, and norank_f_norank_o_Clostridia_UCG-014), and increases the prevalence of pathogenic gut bacteria (Coriobacteriaceae_UCG-002 and Desulfovibrio), exacerbating liver injury through the gut-liver axis. However, administering DHA-PS (50 mg/kg) effectively alleviated these injuries. ConclusionThis study was the first to employ multi-omics techniques to elucidate the potential mechanisms underlying hepatotoxicity induced by PS-NPs, thereby supporting the use of DHA-PS as a dietary supplement to mitigate the effects of nanoplastic pollutants.

Attenuation of chromium (VI) and arsenic (III)-induced oxidative stress and hepatic apoptosis by phloretin, biochanin-A, and coenzyme Q10 via activation of SIRT1/Nrf2/HO-1/NQO1 signaling.

Heavy metal contamination is an alarming concern on a global scale, as drinking tainted water significantly increases human susceptibility to heavy metals. In a realistic scenario, humans are often exposed to a combination of harmful chemicals rather than a single toxicant. Phloretin (PHL), biochanin-A (BCA), and coenzyme Q10 (CoQ10) are bioactive compounds owning plentiful pharmacological properties. Henceforth, the current research explored the putative energizing effects of selected nutraceuticals in combined chromium (Cr) and arsenic (As) intoxicated Swiss albino mice. Potassium dichromate (75 ppm) and sodium meta-arsenite (100 ppm) were given in the drinking water to induce hepatotoxicity, conjugated with PHL and BCA (50 mg/kg each), and CoQ10 (10 mg/kg) intraperitoneally for 2 weeks. After the statistical evaluation, it was observed that the hepato-somatic index, metal load, and antioxidant activity (lipid peroxidation and protein carbonyl content) increased along with the concomitant decrease in the antioxidants (catalase, glutathione-S-transferase, superoxide dismutase, reduced glutathione, and total thiol) in the Cr and As intoxicated mice. Additionally, light microscopy observations, DNA breakages, decreased silent information regulator 1 (SIRT1), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), heme oxygenase (HO-1), and NAD(P)H quinone dehydrogenase 1 (NQO1) gene expressions, together with stimulated apoptotic cell death manifested by the increased expressions of caspase 8 and caspase 3, thus, proved consistency with the aforementioned outcomes. Importantly, the treatment with nutraceuticals not only restored the antioxidant activity but also favorably altered the expressions of SIRT1, Nrf2, HO-1, and NQO1 signaling and apoptosis markers. These findings highlight the crucial role of the PHL, BCA, and CoQ10 combination in reducing Cr and As-induced hepatotoxicity in mice. By averting the triggered apoptosis in conjunction with oxidative stress, this combination increases the SIRT1, Nrf2, HO-1, and NQO1 signaling, thereby reassuringly maintaining the cellular equilibrium.

Empagliflozin impact on experimentally induced acetaminophen toxicity: Imprint of mitochondrial dynamics, biogenesis, and cGAS/STING signal in amending liver insult.

Acetaminophen (APAP) is one of the most clinically relevant medications associated with acute liver damage. A prolific deal of research validated the hepatoprotective effect of empagliflozin (EMPA); however, its effect on APAP-induced hepatotoxicity has still not been investigated. In this study, the prospective hepatoprotective impact of EMPA against APAP-induced hepatotoxicity was investigated. Twenty-eight Balb-C mice were assigned to four groups: control, APAP, EMPA10/APAP, and EMPA25/APAP. At the end of the experiment, serum hepatotoxicity biomarkers, MDA level, and GSH content were estimated. Hepatic mitofusin-2 (MFN2), optic atrophy 1 (OPA1), dynamin-related protein 1 (Drp1), and mitochondrial fission 1 protein (FIS1) were immunoassayed. PGC-1α, cGAS, and STING mRNA expression were assessed by real-time PCR. Histopathological changes and immunohistochemistry of INF-β, p-NF-κB, and iNOS were evaluated. APAP treatment caused significant hepatic functional impairment and increased hepatic MDA levels, as well as a concomitant decrease in GSH content. Marked elevation in Drp1 and FIS1 levels, INF-ß, p-NF-κB, and iNOS immunoreactivity, and reduction in MFN2 and OPA1 levels in the APAP-injected group, PGC-1α downregulation, and high expression of cGAS and STING were also documented. EMPA effectively ameliorated APAP-generated structural and functional changes in the liver, restored redox homeostasis and mitochondrial dynamics balance, and enhanced mitochondrial biogenesis, remarkably diminished hepatic expression of cGAS and STING, and elicited a reduction in hepatic inflammation. Moreover, the computational modeling data support the interaction of APAP with antioxidant system-related proteins as well as the interactions of EMPA against Drp1, cGAS, IKKA, and iNOS proteins. Our findings demonstrated for the first time that EMPA has an ameliorative impact against APAP-induced hepatotoxicity in mice via modulation of mitochondrial dynamics, biogenesis, and cGAS/STING-dependent inflammation. Thus, this study concluded that EMPA could be a promising therapeutic modality for acute liver toxicity.

Anti-Oxidative and Anti-Apoptotic Oligosaccharides from Pichia pastoris-Fermented Cress Polysaccharides Ameliorate Chromium-Induced Liver Toxicity.

Oxidative stress impairs the structure and function of the cell, leading to serious chronic diseases. Antioxidant-based therapeutic and nutritional interventions are usually employed for combating oxidative stress-related disorders, including apoptosis. Here, we investigated the hepatoprotective effect of oligosaccharides, produced through Pichia pastoris-mediated fermentation of water-soluble polysaccharides isolated from Lepidium sativum (cress) seed mucilage, on chromium(VI)-induced oxidative stress and apoptosis in mice. Gel permeation chromatography (GPC), using Bio-Gel P-10 column, of the oligosaccharides product of fermentation revealed that P. pastoris effectively fermented polysaccharides as no long chain polysaccharides were observed. At 200 µg/mL, fractions DF73, DF53, DF72, and DF62 exhibited DPPH radical scavenging activity of 92.22 ± 2.69%, 90.35 ± 0.43%, 88.83 ± 3.36%, and 88.83 ± 3.36%, respectively. The antioxidant potential of the fermentation product was further confirmed through in vitro H2O2 radical scavenging assay. Among the screened samples, the highest H2O2 radical scavenging activity was displayed by DF73, which stabilized the free radicals by 88.83 ± 0.38%, followed by DF53 (86.48 ± 0.83%), DF62 (85.21 ± 6.66%), DF72 (79.9 4± 1.21%), and EPP (77.76 ± 0.53%). The oligosaccharide treatment significantly alleviated chromium-induced liver damage, as evident from the increase in weight gain, improved liver functions, and reduced histopathological alterations in the albino mice. A distinctly increased level of lipid peroxide (LPO) free radicals along with the endogenous hepatic enzymes were evident in chromium induced hepatotoxicity in mice. However, oligosaccharides treatment mitigated these effects by reducing the LPO production and increasing ALT, ALP, and AST levels, probably due to relieving the oxidative stress. DNA fragmentation assays illustrated that Cr(VI) exposure induced massive apoptosis in liver by damaging the DNA which was then remediated by oligosaccharides supplementation. Histopathological observations confirmed that the oligosaccharide treatment reverses the architectural changes in liver induced by chromium. These results suggest that oligosaccharides obtained from cress seed mucilage polysaccharides through P. pastoris fermentation ameliorate the oxidative stress and apoptosis and act as hepatoprotective agent against chromium-induced liver injury.

Bavachinin, a main compound of Psoraleae Fructus, facilitates GSDMD-mediated pyroptosis and causes hepatotoxicity in mice

Psoraleae Fructus (PF, Psoralea corylifolia L.), a traditional medicine with a long history of application, is widely used clinically for the treatment of various diseases. However, the reports of PF-related adverse reactions, such as hepatotoxicity, phototoxic dermatitis, and allergy, are increasing year by year, with liver injury being the mostly common. Our previous studies have demonstrated that PF and its preparations can cause liver injury in lipopolysaccharide (LPS)-mediated susceptibility mouse model, but the mechanism of PF-related liver injury is unclear. In this study, we showed that PF and bavachinin, a major component of PF, can directly induce the expression of caspase-1 and interleukin-1β (IL-1β), indicating that PF and bavachinin can directly triggered the activation of inflammasome. Furthermore, pretreatment with NLR family pyrin domain-containing 3 (NLRP3), NLR family CARD domain containing 4 (NLRC4) or absent in melanoma 2 (AIM2) inflammasome inhibitors, containing MCC950, ODN TTAGGG (ODN) and carnosol, all significantly reversed bavachinin-induced inflammasome activation. Mechanistically, bavachinin dose-dependently promote Gasdermin D (GSDMD) post-shear activation and then induce mitochondrial reactive oxygen species (mtROS) production and this effect is markedly inhibited by pretreatment with N-Acetylcysteine amide (NAC). In addition, combination treatment of LPS and bavachinin significantly induced liver injury in mice, but not LPS or bavachinin alone, and transcriptome analysis further validated these results. Thus, PF and bavachinin can induce the activation of inflammasome by promoting GSDMD cleavage and cause hepatotoxicity in mice. Therefore, PF, bavachinin, and PF-related preparations should be avoided in patients with inflammasome activation-associated diseases.

Attenuation of paracetamol-induced hepatotoxicity in Ajuga bracteosa extract treated mice

Ajuga bracteosa (Ab) has tremendous medicinal value with long-established disease curing potential. The present study aimed to assess the hepatoprotective potential of Ab extracts in paracetamol-induced hepatotoxicity in mice. Group I (normal control) were treated with saline 1 ml/kg BW orally for 7 days while Group II (toxicant control) received saline 1 ml/kg BW for 6 days and Paracetamol (1000 mg/kg BW) on day7of the treatment. Group III received Standard drug silymarin (100 mg/kg BW) for 6 days and Paracetamol (1000 mg/kg BW) on day 7of treatment. Groups IV andV were administered with methanol extract (ME) 200 mg/kg BW and aqueous extract (AE) 1000 mg/kg BW for 6 days and Paracetamol (1000 mg/kg BW) on day 7th of the study. Both extracts showed hepatoprotective potential against the toxic effects of paracetamol, evidenced by serum analysis of biomarkers involved in liver injury and histopathological findings. Hepatotoxic mice pretreated with Ab plant extract or silymarin exhibited significant decrease in ALP, AST, and ALT enzyme level while GSH levels were markedly increased. According to histological observations, groups treated with PCM (toxicant control) showed significant necrosis and lymphocyte infiltration, while groups treated with silymarin and Ajuga bracteosa plant extract showed preservation of the normal liver structural features. The phytochemical analysis of ME and AE of Ab showed the presence of glycosides, phenolic compounds, tannins, fats, saponins, flavonoids, terpenes, oils, and fats. The antioxidant activity of these two extracts was determined by nitric oxide assay, DPPH assay, and ferric reducing power assay. The methanolic extract exhibited the highest antioxidant potential (78.09 ± 0.0806). The antioxidant potential of aqueous extract was 73.08 ± 0.248. The reducing power for methanolic extract and ascorbic acid (standard) 500 μg/ml was 0.933 and 0.987 respectively. The anti-inflammatory activity of both extracts was demonstrated by in vitro methods, namely albumin denaturation, proteinase inhibition, and membrane stabilization assays. The study suggests that Ab extracts have competence for attenuating inflammation, oxidants, and hepatotoxicity.

Effects of 6PPD-Quinone on Human Liver Cell Lines as Revealed with Cell Viability Assay and Metabolomics Analysis.

N-(1,3-Dimethyl butyl)-N'-phenyl-phenylenediamine-quinone (6PPD-Q) is a derivative of the widely used rubber tire antioxidant 6PPD, which was first found to be acutely toxic to coho salmon. Subsequent studies showed that 6PPD-Q had species-specific acute toxicity in fishes and potential hepatotoxicity in mice. In addition, 6PPD-Q has been reported in human urine, demonstrating the potential widespread exposure of humans to this chemical. However, whether 6PPD-Q poses a higher risk to humans than its parent compound, 6PPD, and could cause adverse effects in humans is still unclear. In this study, we utilized two human liver cell models (the human proto-hepatocyte model L02 and the human hepatocellular carcinoma cell line HepG2) to investigate the potentially differential effects of these two chemicals. Cell viability curve analysis showed that 6PPD-Q had lower IC50 values than 6PPD for both liver cell lines, suggesting higher toxicity of 6PPD-Q to human liver cells than 6PPD. In addition, L02 cells are more sensitive to 6PPD-Q exposure, which might be derived from its weaker metabolic transformation of 6PPD-Q, since significantly lower levels of phase I and phase II metabolites were detected in 6PPD-Q-exposed L02 cell culture medium. Furthermore, pathway analysis showed that 6PPD-Q exposure induced changes in phenylalanine, tyrosine, and tryptophan biosynthesis and tyrosine metabolism pathways in L02 cells, which might be the mechanism underlying its liver cell toxicity. Gene expression analysis revealed that exposure to 6PPD-Q induced excessive ROS production in L02 cells. Our results further supported the higher risk of 6PPD-Q than 6PPD and provided insights for understanding the effects of 6PPD-Q on human health.

Deletion of Glyoxalase 1 Exacerbates Acetaminophen-Induced Hepatotoxicity in Mice.

Acetaminophen (APAP) overdose triggers a cascade of intracellular oxidative stress events, culminating in acute liver injury. The clinically used antidote, N-acetylcysteine (NAC), has a narrow therapeutic window, and early treatment is essential for a satisfactory therapeutic outcome. For more versatile therapies that can be effective even at late presentation, the intricacies of APAP-induced hepatotoxicity must be better understood. Accumulation of advanced glycation end products (AGEs) and the consequent activation of the receptor for AGEs (RAGE) are considered one of the key mechanistic features of APAP toxicity. Glyoxalase 1 (Glo-1) regulates AGE formation by limiting the levels of methylglyoxal (MEG). In this study, we studied the relevance of Glo-1 in the APAP-mediated activation of RAGE and downstream cell death cascades. Constitutive Glo-1-knockout mice (GKO) and a cofactor of Glo-1, ψ-GSH, were used as tools. Our findings showed elevated oxidative stress resulting from the activation of RAGE and hepatocyte necrosis through steatosis in GKO mice treated with high-dose APAP compared to wild-type controls. A unique feature of the hepatic necrosis in GKO mice was the appearance of microvesicular steatosis as a result of centrilobular necrosis, rather than the inflammation seen in the wild type. The GSH surrogate and general antioxidant ψ-GSH alleviated APAP toxicity irrespective of the Glo-1 status, suggesting that oxidative stress is the primary driver of APAP toxicity. Overall, the exacerbation of APAP hepatotoxicity in GKO mice suggests the importance of this enzyme system in antioxidant defense against the initial stages of APAP overdose.

Wogonin mitigates acetaminophen-induced liver injury in mice through inhibition of the PI3K/AKT signaling pathway

Ethnopharmacological relevanceScutellaria baicalensis Georgi (SBG), a widely used traditional Chinese medicine, exhibits anti-inflammatory and antioxidant properties. Wogonin is one of the primary bioactive components of SBG. Acetaminophen (APAP)-induced liver injury (AILI) represents a prevalent form of drug-induced liver damage and is primarily driven by inflammatory responses and oxidative stress. Aim of studyTo investigate the therapeutic effects of Wogonin on AILI and the underlying mechanisms. Materials and methodsC57BL/6 J mice were pre-treated with Wogonin (1, 2.5, and 5 mg/kg bodyweight) for 3 days, followed by treatment with APAP (300 mg/kg bodyweight). The serum and liver tissue samples were collected at 24 h post-APAP treatment. Bone marrow-derived macrophages and RAW264.7 cells were cultured and pre-treated with Wogonin (5, 10, and 20 μM) for 30 min, followed by stimulation with lipopolysaccharide (LPS; 100 ng/mL) for 3 h. To examine the role of the PI3K/AKT signaling pathway in the therapeutic effect of Wogonin on AILI, mice and cells were treated with LY294002 (a PI3K inhibitor) and MK2206 (an AKT inhibitor). ResultsWogonin pre-treatment dose-dependently alleviated AILI in mice. Additionally, Wogonin suppressed oxidative stress and inflammatory responses. Liver transcriptome analysis indicated that Wogonin primarily regulates immune function and cytokines in AILI. Wogonin suppressed inflammatory responses of macrophages by inhibiting the PI3K/AKT signaling pathway. Consistently, Wogonin exerted therapeutic effects on AILI in mice through the PI3K/AKT signaling pathway. ConclusionsWogonin alleviated AILI and APAP-induced hepatotoxicity in mice through the PI3K/AKT signaling pathway.

Integrating metabolomics and network toxicology to reveal the mechanism of hypoaconitine-induced hepatotoxicity in mice

Hypoaconitine (HA), a major secondary metabolite of aconite (a plant-derived rodenticide), is a highly toxic di-ester alkaloidal constituent. The toxicity of HA is intense with a low LD50. However, studies on its toxicity mechanism have mainly focused on cardiotoxicity, with few reports on the mechanism of hepatotoxicity. In this study, we combined metabolomics and network toxicology to investigate the effects of HA on the liver and analyzed the mechanisms by which it causes hepatotoxicity. The results of metabolomics studies indicated diethylphosphate, sphingosine-1-phosphate, glycerophosphorylcholine, 2,8-quinolinediol, guanidinosuccinic acid, and D-proline as differential metabolites after HA exposure. These metabolites are involved in eight metabolic pathways including arginine and proline metabolism, ether lipid metabolism, β-alanine metabolism, sphingolipid metabolism, glutathione metabolism, and glycerophospholipid metabolism. Network toxicology analysis of HA may affect the HIF-1 signaling pathway, IL-17 signaling pathway, PI3K-Akt signaling pathway, MAPK signaling pathway, and so on by regulating the targets of ALB, HSP90AA1, MMP9, CASP3, and so on. Integrating the results of metabolomics and network toxicology, it was concluded that HA may induce hepatotoxicity by triggering physiological processes such as oxidative stress, inflammatory response, and inducing apoptosis in hepatocytes.

KLF15-Cyp3a11 Axis Regulates Rifampicin-Induced Liver Injury.

Rifampicin (RFP) has demonstrated potent antibacterial effects in the treatment of pulmonary tuberculosis. However, the serious adverse effects on the liver intensively limit the clinical usage of the drug. Deacetylation greatly reduces the toxicity of RFP but also retains its curative activity. Here, we found that Krüppel-like factor 15 (KLF15) repressed the expression of the major RFP detoxification enzyme Cyp3a11 in mice via both direct and indirect mechanisms. Knockout of hepatocyte KLF15 induced the expression of Cyp3a11 and robustly attenuated the hepatotoxicity of RFP in mice. In contrast, overexpression of hepatic KLF15 exacerbated RFP-induced liver injury as well as mortality. More importantly, the suppression of hepatic KLF15 expression strikingly restored liver functions in mice even after being pretreated with overdosed RFP. Therefore, this study identified the KLF15-Cyp3a11 axis as a novel regulatory pathway that may play an essential role in the detoxification of RFP and associated liver injury. SIGNIFICANCE STATEMENT: Rifampicin has demonstrated antibacterial effects in the treatment of pulmonary tuberculosis. However, the serious adverse effects on the liver limit the clinical usage of the drug. Permanent depletion and transient inhibition of hepatic KLF15 expression significantly induced the expression of Cyp3a11 and robustly attenuated mouse hepatotoxicity induced by RFP. Overall, our studies show the KLF15-Cyp3a11 axis was identified as a novel regulatory pathway that may play an essential role in the detoxification of RFP and associated liver injury.

Turmeric Extract-loaded Selenium Nanoparticles Counter Doxorubicin-induced Hepatotoxicity in Mice via Repressing Oxidative Stress, Inflammatory Cytokines, and Cell Apoptosis.

Doxorubicin (DOX) is an antitumor anthracycline used to treat a variety of malignancies; however, its clinical use is associated with noticeable hepatotoxicity. Therefore, the current study was designed to delineate if biosynthesized SeNPs with turmeric extract (Tur-SeNPs) could alleviate DOX-induced hepatic adverse effects. Mice were orally post-treated with Tur extract, Tur-SeNPs, or N-acetyl cysteine after the intraperitoneal injection of DOX. Our findings have unveiled a remarkable liver attenuating effect in DOX-injected mice post-treated with Tur-SeNPs. High serum levels of ALT, AST, ALP, and total bilirubin induced by DOX were significantly decreased by Tur-SeNPs therapy. Furthermore, Tur-SeNPs counteracted DOX-caused hepatic oxidative stress, indicated by decreased MDA and NO levels along with elevated levels of SOD, CAT, GPx, GR, GSH, and mRNA expression levels of Nrf-2. Noteworthily, decreased hepatic IL-1β, TNF-α, and NF-κB p65 levels in addition to downregulated iNOS gene expression in Tur-SeNPs-treated mice have indicated their potent antiinflammatory impact. Post-treatment with Tur-SeNPs also mitigated the hepatic apoptosis evoked by DOX injection. A liver histological examination confirmed the biochemical and molecular findings. In brief, the outcomes have demonstrated Tur loaded with nanoselenium to successfully mitigate the liver damage induced by DOX via blocking oxidative stress, and inflammatory and apoptotic signaling.

Phytochemical profile, anti-oxidant and hepatoprotective activity Ocimum tenuiflorum leaves against carbon tetrachloride–induced hepatotoxicity in Mice

Ocimum tenuiflorum is a medicinal plant with therapeutic potential, belongs to the family Lamiaceae also known as, tulsi and is known for its anti-oxidant and hepatoprotective activity. I have been selected groups were divided into two different doses, test groups (200 and 400 mg/kg) of the crude extracts, the standard drug (silymarin 100 mg/kg), and the hepatotoxicant carbone tetrachloride was negative control. The result of anti-oxidant and hepatoprotective activity suggested that effects of Ocimum tenuiflorum leaves extract were tested on phytochemical, results showed the presence of alkaloid, saponins, steroid, phenolic compounds flavonoids, tannins as chemical constituents may have anti-oxidant and hepatoprotective activity, which is not evaluated till now.Amoung the results, shows The amount of steroids was estimated to be 11.85 mg/g and 57.69 mg/g respectively for methanol extracts respectively. The amount of alkaloids was estimated to be 121.69 mg/g and 12.30 mg/g respectively for methanol extracts respectively. The amount of phenolic compounds was estimated to be 71.32 mg/g for methanol extract. The amount of flavonoids was estimated to be 116.60 mg/g respectively for methanol extracts respectively. The IC50 concentration of methanol extract was noticed to be very close to standard suggest that the activity of methanol extract was very high. The 80% methanol extract decreased the absolute and relative weight of the liver of mice at the doses of 200 and 400 mg/kg (p&lt; 0.01 and p&lt; 0.001, respectively). It also suppressed the plasma levels of AST and ALT (p&lt; 0.001) in the aforementioned doses. Among extracts, the methanol fraction showed maximum hepatoprotective activity in its dose of 400 mg/kg (p&lt; 0.001, in all cases). Ocimum tenuiflorum is endowed with hepatoprotectiveactivity, probably mediated via its antioxidant and anti-inflammatory activity. Thus, Ocimum tenuiflorum can be taken as one candidate for the development of hepatoprotective agents because of its good safety profile.